Insights into Ebola Virus VP35 and VP24 Interferon Inhibitory Functions and their Initial Exploitation as Drug Targets

Fanunza, Elisa; Frau, Aldo; Corona, Angela; Tramontano, Enzo

doi:10.2174/1871526519666181123145540

Cited by 22 publications

(19 citation statements)

References 138 publications

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“…In addition to the ubiquitination-dependent modulation of host immune responses discussed above, we find ubiquitin-dependent degradation to be targeted by SARS-CoV-2. Hijacking the ubiquitin proteasome system is a common trait of almost all viruses (Banks et al, 2003;Fanunza et al, 2019;Tang et al, 2018). Supporting the idea that this is occurring for SARS-CoV-2, we found SARS-CoV-2 viral proteins to target host proteins involved in ubiquitin-mediated degradation.…”

Section: Functions Enriched In a Sars-cov-2/human Virhostome Networksupporting

confidence: 80%

A map of binary SARS-CoV-2 protein interactions implicates host immune regulation and ubiquitination

Kim

Weller

Lin

et al. 2021

Preprint

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Key steps in viral propagation, immune suppression and pathology are mediated by direct, binary physical interactions between viral and host proteins. To understand the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated an unbiased systematic map of binary physical interactions between viral and host interactions, complementing previous co-complex association maps by conveying more direct mechanistic understanding and enabling targeted disruption of direct interactions. To this end, we deployed two parallel strategies, identifying 205 virus-host and 27 intraviral binary interactions amongst 171 host and 19 viral proteins, with orthogonal validation by an internally benchmarked NanoLuc two-hybrid system to ensure high data quality. Host proteins interacting with SARS-CoV-2 proteins were enriched in various cellular processes, including immune signaling and inflammation, protein ubiquitination, and membrane trafficking. Specific subnetworks provide new hypotheses related to viral modulation of host protein homeostasis and T-cell regulation. The direct virus-host protein interactions we identified can now be prioritized as targets for therapeutic intervention. More generally, we provide a resource of systematic maps describing which SARS-CoV-2 and human proteins interact directly.

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Section: Functions Enriched In a Sars-cov-2/human Virhostome Networksupporting

confidence: 80%

A map of binary SARS-CoV-2 protein interactions implicates host immune regulation and ubiquitination

Kim

Weller

Lin

et al. 2021

Preprint

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“…1,12,13 The ability of EBOV to avoid and inhibit the innate immune response in the early stages of infection is due to the viral multifunctional proteins, VP24 and VP35, 14,15 which are the main determinants of virulence 16–18 and thus attractive drug targets. 19–24…”

Section: Introductionmentioning

confidence: 99%

Relevance of Ebola virus VP35 homo-dimerization on the type I interferon cascade inhibition

Palma

Daino

Ramaswamy

et al. 2019

Antivir Chem Chemother

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Ebola virus high lethality relies on its ability to efficiently bypass the host innate antiviral response, which senses the viral dsRNA through the RIG-I receptor and induces type I interferon a/b production. In the bypassing action, the Ebola virus protein VP35 plays a pivotal role at multiple levels of the RIG-I cascade, masking the viral 5 0-triphosphorylated dsRNA from RIG-I, and interacting with other cascade components. The VP35 type I interferon inhibition is exerted by the C-terminal domain, while the N-terminal domain, containing a coiled-coil region, is primarily required for oligomerization. However, mutations at key VP35 residues L90/93/107A (VP35-3m) in the coiled-coil region were reported to affect oligomerization and reduce type I interferon antagonism, indicating a possible but unclear role of homo-oligomerization on VP35 interaction with the RIG-I pathway components. In this work, we investigated the VP35 dimerization thermodynamics and its contribution to type I interferon antagonism by computational and biological methods. Focusing on the coiled-coil region, we combined coarse-grained and all-atom simulations on wild type VP35 and VP35-3m homo-dimerization. According to our results, wild type VP35 coiled-coil is able to self-assemble into dimers, while VP35-3m coiled-coil shows poor propensity to even dimerize. Free-energy calculations confirmed the key role of L90, L93 and L107 in stabilizing the coiled-coil homo-dimeric structure. In vitro type I interferon antagonism studies, using full-length wild type VP35 and VP35-3m, revealed that VP35 homo-dimerization is an essential preliminary step for dsRNA binding, which appears to be the main factor of the VP35 RIG-I cascade inhibition, while it is not essential to block the other steps.

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“…Mutations of VP24 residues involved in the suppression of the IFN cascade were shown to be responsible for the acquisition of high virulence in animal models (5,10), suggesting VP24 as a validated target for drug development. Hence, identifying a therapy targeting the IFN-I-inhibitory functions of EBOV represents a promising approach to an early control of the infection (11)(12)(13)(14). A number of in silico studies reported molecules potentially able to bind different EBOV targets, including VP24 (15,16), while two recent studies reported that a macrocyclic peptide and a nucleic acid aptamer could antagonize the binding of VP24 and KPN␣ in biochemical assays (17,18).…”

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confidence: 99%

Quercetin Blocks Ebola Virus Infection by Counteracting the VP24 Interferon-Inhibitory Function

Fanunza

Iampietro

Distinto

et al. 2020

Antimicrob Agents Chemother

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Ebola virus (EBOV) is among the most devastating pathogens causing fatal hemorrhagic fever in humans. The epidemics from 2013 to 2016 resulted in more than 11,000 deaths, and another outbreak is currently ongoing. Since there is no FDA-approved drug so far to fight EBOV infection, there is an urgent need to focus on drug discovery. Considering the tight correlation between the high EBOV virulence and its ability to suppress the type I interferon (IFN-I) system, identifying molecules targeting viral protein VP24, one of the main virulence determinants blocking the IFN response, is a promising novel anti-EBOV therapy approach. Hence, in the effort to find novel EBOV inhibitors, a screening of a small set of flavonoids was performed; it showed that quercetin and wogonin can suppress the VP24 effect on IFN-I signaling inhibition. The mechanism of action of the most active compound, quercetin, showing a half-maximal inhibitory concentration (IC50) of 7.4 μM, was characterized to significantly restore the IFN-I signaling cascade, blocked by VP24, by directly interfering with the VP24 binding to karyopherin-α and thus restoring P-STAT1 nuclear transport and IFN gene transcription. Quercetin significantly blocked viral infection, specifically targeting EBOV VP24 anti-IFN-I function. Overall, quercetin is the first identified inhibitor of the EBOV VP24 anti-IFN function, representing a molecule interacting with a viral binding site that is very promising for further drug development aiming to block EBOV infection at the early steps.

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Insights into Ebola Virus VP35 and VP24 Interferon Inhibitory Functions and their Initial Exploitation as Drug Targets

Cited by 22 publications

References 138 publications

A map of binary SARS-CoV-2 protein interactions implicates host immune regulation and ubiquitination

A map of binary SARS-CoV-2 protein interactions implicates host immune regulation and ubiquitination

Relevance of Ebola virus VP35 homo-dimerization on the type I interferon cascade inhibition

Quercetin Blocks Ebola Virus Infection by Counteracting the VP24 Interferon-Inhibitory Function

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